Noise-Induced Hearing Loss: Threshold, exposure and genetic susceptibility

描述（由申请人提供）：这个R21转化研究基金PAR 06-095申请的短期目标，题为“噪音诱发的听力损失：阈值，暴露和遗传易感性”，是建立一个基础，以确定对噪音诱发的听力损失（NIHL）表现出遗传易感性的人。该申请是由一个由三名研究人员组成的团队提出的：PI是听力学博士苏珊·l·菲利普斯（Susan L. Phillips），她与共同PI的遗传学博士文森特·c·亨利希（Vincent C. Henrich）、统计学博士斯科特·j·里希特（Scott J. Richter）和音乐教育博士、认证听力保护专家桑德拉·t·梅斯（Sandra T. Mace）合作。众所周知，过度接触声音会导致噪音性听力损失。然而，即使在没有经历过异常水平声学暴露的受试者中，NIHL也存在相当大的差异，因此，我们对谁是NIHL风险最大的人以及谁不是NIHL风险最大的人的认识存在重大差距。该项目将通过确定与NIHL遗传易感性相关的关键变量来填补知识空白。到目前为止，我们研究中确定的关键变量包括听力学特征（单侧或双侧，缺口深度和频率），报告的当前和过去的声暴露以及测量的声暴露（强度和持续时间）。具体目的是：1)比较在先前研究中发现的与NIHL相关的几个基因位点上存在双侧、单侧或无缺口变异的受试者的原始患病率和调整后的患病率。根据Phillips等人提出的标准，工作假设是双侧缺口个体中NIHL易感等位基因的频率高于单侧缺口或无缺口个体。2)检查是否存在显著的基因-环境相互作用。工作假设是，当前暴露量最高且携带NIHL易感等位基因的个体将表现出NIHL的最大进展。我们将在一项涉及1000名年龄在18-25岁之间的学生的研究中对阈值和暴露水平进行直接和间接测量，使我们能够避免在其他NIHL遗传关联研究中出现的混淆。这些因素包括与年龄有关的听力损失和可能导致听力损失的疾病因素，可能导致听力损失的额外化学品接触，以及与工业人口有关的极端接触和接触时间。以前的研究发现，有必要对这些混杂因素进行统计校正，而且人们承认，这些校正会使数据的解释变得复杂（Konings等人，2009）。将从三组学生中收集颊细胞并提取DNA：有双侧缺口的学生，有单侧缺口的学生和没有缺口的对照组。该项目与公共卫生的相关性反映在我们的长期目标中，即利用对NIHL的机制理解，制定个性化的NIHL预防计划，使用标准的临床听力学测试作为遗传易感性指标。在早期识别高危人群和暴露情况的能力，可能通过制定NIHL风险概况，将使卫生保健提供者，音乐教育者，工业和军事听力保护主义者以及其他人能够针对高危人群采取预防措施。预防措施包括教育、使用听力保护装置、对接触地点进行减声改造以及监测接触强度和持续时间。

DESCRIPTION (provided by applicant): The short-term goal of this R21 Translational Research Grant PAR 06-095 application, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss (NIHL). The application is proposed by a team of three researchers: The PI is Susan L. Phillips, Ph.D. in audiology (CCC-A), who is working with Co-PI's Vincent C. Henrich, Ph.D. in genetics, Scott J. Richter, Ph.D. in statistics and Sandra T. Mace, Ph.D. in music education and certified Hearing Conservation Specialist. It is known that acoustic overexposure can cause noise-induced hearing loss. Nevertheless, there is considerable variability in NIHL even among subjects who have not experienced unusual levels of acoustic exposure, and, thus, there is a critical gap in our knowledge about who is and is not most at risk for NIHL. This project will fill the gap in knowledge by identifying the critical variables associated with a genetic predisposition to NIHL. Critical variables identified in our study so far include the audiological profile (unilateral or bilateral, depth of notch and frequency of notch), reported current and past acoustic exposure and measured acoustic exposure (intensity and duration). The Specific Aims are: 1) Compare the crude and adjusted prevalence among subjects with bilateral, unilateral, or no notches of variants at several gene loci found in previous research to be associated with NIHL. Based on criteria laid out in Phillips et al. (in press), the working hypothesis will be that the frequency of predisposing alleles for NIHL will be higher among individuals with bilateral notches than in those with unilateral or no notches. 2) Examine whether there are significant gene-environment interactions present. The working hypothesis will be that the individuals with the highest current exposure and carrying predisposing alleles to NIHL will show the greatest progression of NIHL. We will make direct and indirect measurements of thresholds and exposure levels in a study involving 1,000 students between the ages of 18-25 years, allowing us to avoid the confounds present in other genetic association studies of NIHL. These include age-related hearing loss and disease factors that can contribute to hearing loss, additional chemical exposures that can contribute to hearing loss, and the extreme exposures and exposure durations associated with industrial populations. Previous studies have found it necessary to apply statistical corrections for these confounds and the corrections were acknowledged to have complicated the interpretation of the data (Konings et al., 2009). Buccal cells will be collected and DNA extracted from students in three groups: those with bilateral notches, with unilateral notches, and a control group of students with no notches. The project's relevance to public health is reflected in our long-term goal, which is to use a mechanistic understanding of NIHL to develop a personalized NIHL prevention program using standard clinical audiological tests as indicators of genetic susceptibility. The ability to identify at-risk individuals and exposure situations at an early age, perhaps through the development of a NIHL Risk Profile, will allow health care providers, music educators, industrial and military hearing conservationists, and others to target preventive measures to at-risk individuals. Preventive measures include education, the use of hearing protection devices, sound attenuation modifications to exposure sites and monitoring of exposure intensities and durations. PUBLIC HEALTH RELEVANCE: NIHL is a growing health concern among children, found in 15.5% aged 12-19 (Niskar et al., 2001), in 28% of college students who listen to personal listening devices (Mostafpour et al., 1998), and 44% of student musicians in a university School of Music (Phillips et al., in press). The short-term goal of this application for an R21 Translational Research Grant PAR 06-095, entitled "Noise-induced hearing loss: threshold, exposure, and genetic susceptibility," is to establish a basis for identifying people showing a genetic susceptibility to noise-induced hearing loss. The relevance of the project to public health is reflected in the long-term goal, which is to use a mechanistic understanding of noise-induced hearing loss to develop a personalized prevention program using standard clinical audiological tests as indicators of genetic susceptibility.